The current obesity epidemic in the US is the major contributor to the soaring rates of metabolic diseases and to skyrocketing health care costs. Yet the molecular and pathological mechanisms by which obesity induces metabolic disorders remain incompletely understood, and therapeutic interventions for obesity and related metabolic abnormalities are limited. In recent years, thousands of long non-coding RNAs lncRNAs have been identified and constitutes a significant portion of mammalian genomes. Interestingly, half of SNPs associated with diseases including metabolic disease fall in the noncoding regions suggesting that dysfunction of lncRNAs might be pathogenic. However, the pathophysiological roles of most lncRNAs remain poorly understood and their implications in metabolic disorder are largely unexplored. To systemically identify lncRNAs that might be involved in metabolic regulation, we performed genome-wide screens to compare lncRNA profiles in a variety of mouse models with defective systemic lipid or glucose metabolism. These screens identified thousands of lncRNAs whose expressions were strongly regulated by metabolic conditions or in mice with metabolic disorders. We have recently demonstarted that a liver-enriched lncRNA robustly reuglates systemic lipid metaoblism in vivo (Li et al, Cell Metabolism. 2015) and several lncRNAs regulate critical aspects of glucose and cholesterol metabolism in healthy and diseased mice. To further investigate the molecular basis by which the selected lncRNAs regulates engery metabolism, we have generated mice with tissue-specific loss-of-function of lncRNAs, and have carried out extensive analyses to determine signaling and metabolic pathways impacted by these lncRNAs. In addition, we are also pursuing the pathological role of lncRNAs in human hepatocytes carrying mutations that cause metabolic disorders.